We submit this application in response to PAR-18-519 ?Sensory and motor system changes as predictors of preclinical Alzheimer?s disease?. Our goal is to compare the auditory, olfaction, and motor correlates of Alzheimer?s disease (AD) biomarkers of Amyloid, Tau, and Neurodegeneration (ATN) and cognitive performance in community dwelling adults in late middle age. Our application addresses the following interest areas delineated in PAR-18-519: ?Mechanistic studies to understand if and how early AD pathology in sensory and/or motor areas of the CNS can contribute to decline in sensory/motor function? and ?Clinical Studies combining sensory and/or motor system measures with other molecular, genetic, and/or imaging biomarkers of AD risk to identify a battery that might predict conversion to AD?. The field of AD research has mainly focused on cognitive test performance as a surrogate clinical marker of AD neuropathology and predictor of dementia risk. While there is growing interest in early sensory and motor markers as correlates of AD neuropathology and predictors of cognitive decline and dementia, most studies assess these predictors in isolation, and mostly when AD neuropathology and cognitive impairment are in an advanced stage. We propose to overcome these issues by adding yearly assessments of olfaction, hearing, motor function, and cognition, to a multiethnic cohort of 500 persons aged 55 to 69 years in Northern Manhattan that is already funded to conduct longitudinal assessments of in-vivo AD biomarkers of ATN biomarkers and comprehensive cognitive testing, at two-time points with 24-month intervals. Our overarching hypothesis is that AD, measured by ATN biomarkers, is correlated with performance in tests of hearing, olfaction, motor function, all of which correlate with cognitive performance. In addition, we hypothesize that CVD exacerbates the associations for cognitive performance and motor function, while CVD?s role in olfaction and hearing is uncertain and may be of less importance. Our primary aim is to study the cross-sectional and longitudinal relation of ATN AD biomarkers with olfaction, hearing and motor performance. We will relate whole brain amyloid (18F-Florbetaben) standardized uptake volume ratio (SUVR), medial and inferior temporal lobe tau (18F-MK6240) SUVR, and entorhinal cortical thickness, to olfactory (BSIT performance), hearing (audiometry performance), and motor function (gait speed, walking speed reserve, gait variability). We will also study the associations among olfaction, hearing, and motor function, and of these with cognitive performance (total recall of the selective reminding test). We will compare the trajectories of hearing, olfaction, motor, and cognitive function in relation to ATN biomarkers. We will examine CVD as both a confounder and moderator in these relationships.